Coexpression with auxiliary β subunits modulates the action of tefluthrin on rat Nav1.6 and Nav1.3 sodium channels

We expressed the rat Na(v)l.3 and Na(v)1.6 sodium channel alpha subunit isoforms in Xenopus oocytes either alone or with the rat beta 1 and beta 2 auxiliary subunits in various combinations and assessed the sensitivity of the expressed channels to resting and use-dependent modification by the pyrethroid insecticide tefluthrin using the two-electrode voltage clamp technique. Coexpression with the beta 1 and beta 2 subunits, either individually or in combination, did not affecting the resting sensitivity of Na(v)1.6 channels to tefluthrin. Modification by tefluthrin of Na(v)1.6 channels in the absence of beta subunits was not altered by the application of trains of high-frequency depolarizing prepulses. By contrast, coexpression of the Na(v)1.6 channel with the beta 1 subunit enhanced the extent of channel modification 2-fold following repeated depolarization. Coexpression of Na(v)1.6 with the beta 2 subunit also slightly enhanced modification following repeated depolarization, but coexpression of Na(v)1.6 with both beta subunits caused enhanced modification following repeated depolarization that was indistinguishable from that found with Na(v)1.6 + beta 1 channels. In contrast to Na(v)1.6, the resting modification by tefluthrin of Na(v)1.3 channels expressed in the absence of beta subunits was reduced by repeated depolarization. However, tefluthrin modification of the Na(v)1.3 alpha subunit expressed with both beta subunits was enhanced 1.7-fold by repeated depolarization, thereby confirming that beta subunit modulation of use-dependent effects was not confined to the Na(v)1.6 isoform. These results show that the actions of pyrethroids on mammalian sodium channels in the Xenopus oocyte expression system are determined in part by the interactions of the sodium channel alpha subunit with the auxiliary beta subunits that are part of the heteromultimeric sodium channel complexes found in neurons and other excitable cells. (C) 2011 Elsevier Inc. All rights reserved.